Although it is accepted as dogma that iron deficiency during development is associated with hypomyelination, the actual data that led to this concept are minimal. In addition, whether any change in myelin quantity or quality is directly or indirectly mediated by iron has not been established. In this proposal we unite the expertise of foreign investigator, Dr. Pasquini, in myelin analysis with the expertise in iron neurobiology of US investigator, Dr. Connor to address the significant clinical question of the role of iron in myelin production and maintenance. The World Health Organization has identified iron deficiency as the number one health disorder. Argentina, the foreign site in this application, has an incidence of iron deficiency in infants that reaches 60%. Iron deficiency is not only from dietary insufficiency, but also stems from the high incidence of parasitic infections in many Latin American children. Three novel animal models are presented in this proposal for analysis, each representing a unique defect in iron metabolism. There are three aims in the proposal. The working hypothesis that unites the three unique animal models is that inadequate iron availability is associated with a uniform decrease in all components of myelin. If the outcome is consistent with our hypothesis, the data will indicate that the role of iron in myelin production is to serve as a metabolic fuel to support the energy required to maintain myelin. If the data are inconsistent with our hypothesis and there are specific components of myelin that are affected relative to the others, the data will suggest a specific role for iron in the synthesis or processing of that component. The future directions would be to move to a cell culture model to directly test the effect of iron. The second aim will use the neonatal hypoxic/ischemic insult model to test the hypothesis that iron status of white matter affects the outcome of the insult. The third aim will test the hypothesis that intracranial injections of transferrin, the iron mobilization protein, will correct myelin deficits in the experimental models used in Aims 1 and 2. The data generated from the studies in this proposal will be novel and will lead to new insights into the specific role of iron in myelin production, maintenance and damage. The data could lead to a possible therapeutic strategy for dysmyelinating disorders. The proposed research will be primarily performed in Argentina through the University of Buenos Aries as an extension of NIH grants PO1 HD30704-08, P01 and HD39386-03.